Inflammation is a cytokine-driven response by the innate immune system to destroy for example pathogens and damaged cells. In some disease conditions, such as rheumatoid arthritis (RA) and Crohn's disease, the regulation of the inflammatory system is impaired leading to tissue damages. Among the most studied inducers of inflammation are the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF). Different inhibitors of TNF are available for clinical use, such as the anti-TNF monoclonal antibodies adalimumab (HUMIRA) and infliximab (REMICADE) as well as the TNF receptor 2-Fc fusion etanercept (ENBREL). The antibody tocilizumab (ACTEMRA), which binds to the IL-6 receptor α (IL-6Rα) rather than the cytokine itself, has been approved for clinical use for IL-6 related disorders. The choice between an IL-6 or TNF blocking anti-inflammatory therapeutic strategy for treating RA is not trivial. Whereas anti-TNF strategies have so far been considered as standard (Taylor and Feldmann, 2009, Nature Reviews Rheumatology 5:578-582), a recent shoulder-to-shoulder monotherapy phase IV trial (ADACTA) in RA patients showed that tocilizumab was more effective than adalimumab in reducing RA-related symptoms (Gabay et al, 2013, Lancet 381:1541-1550).
Human IL-6 consists of a single polypeptide chain of 184 amino acids with a molecular weight of 21 kDa, however a variable glycosylation pattern accounts for sizes varying between 21-26 kDa. IL-6 is secreted by a wide variety of cell types including T cells, B cells, monocytes, fibroblasts, hepatocytes, endothelial cells and keratinocytes. Downstream signaling induces the transition from acute inflammation to either acquired immunity or chronic inflammatory disease. IL-6 signaling and its regulation is complex and involves a number of factors and mechanisms. IL-6 signals via the classical IL-6 signaling pathway, also known as the cis-signaling pathway, or via the trans-signaling pathway. In the classical IL-6 signaling pathway, circulating IL-6 binds to a membrane bound IL-6 receptor α (IL-6Rα) followed by recruitment of the membrane anchored gp130 co-receptor, which results in the formation of a ternary complex. This complex subsequently dimerizes with a second adjacent ternary complex leading to signal transduction via the gp130 moieties (Boulanger et al., 2003, Science 300(5628): 2101-2104). In circulation, IL-6 can also exist bound to soluble ectodomains of IL-6Rα. Such complexes are responsible for the trans-signaling mechanism, involving IL-6 dependent activation of any cells that express the co-receptor gp130 but lack IL-6Rα (Chalaris et al, 2011, Eur J Cell Biol 90(6-7): 484-494; Assier et al, 2010, Joint Bone Spine 77(6):532-6). The trans-signaling, or pro-inflammatory, pathway has been suggested to be the pathway most related to disease conditions, and thus blocking of said pathway is of high interest. In contrast, the classical pathway is regarded to be responsible for important anti-inflammatory and regenerative processes (Scheller et al, 2011, Biochim Biophys Acta 1813(5): 878-888). Other drug candidates, in addition to tocilizumab, are being developed in order to address different IL-6 triggered pathways. These include the antibodies CNTO136 (sirukumab) (Xu et al, 2011, Br J Clin Pharmacol 72(2):270-281; Zhuang et al, 2013, Int J Clin Pharmacol Ther 51(3):187-199) and MEDI5117 (Finch et al, 2011, J Mol Biol 411(4):791-807), which both bind to the IL-6 cytokine itself, as well as a gp130-Fc fusion CR5/18 aimed at selectively blocking the trans-signaling pathway (Kopf et al, 2010, Nat Rev Drug Discov 9(9):703-718, Chalaris et al, 2012, Dig Dis 30(5):492-499).
Recently, considerable progress has been made in the development of antibodies with ability to bind to more than one antigen, for example through engineering of the complementarity determining regions (CDRs) to address two antigens in a single antibody combining site (Bostrom et al, 2009, Science 323(5921):1610-1614, Schaefer et al, 2011, Cancer Cell 20(4):472-486), via construction of heterodimeric antibodies using engineered Fc units (Carter, 2001, J Immunol Methods 248(1-2):7-15; Schaefer et al, 2011, Proc Natl Acad Sci USA 108(27):11187-11192) and via genetic fusion of auxiliary recognition units to N- or C-termini of light or heavy chains of full-length antibodies (Kanakaraj et al, 2012, MAbs 4(5):600-613; LaFleur et al, 2013, MAbs 5(2):208-218).
Thus, there is a high unmet medical need that warrants the development of new modes of treatment for inflammatory and autoimmune disorders, such as for example various forms of rheumatoid arthritis and psoriasis, by blocking more than one factor associated with inflammatory and autoimmune disorders. The provision of agents with dual or even multiple affinity, such as agents with a high affinity for IL-6 and for one or more additional factor(s) associated with inflammatory and autoimmune disorders, is of high importance.